Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study

Am J Respir Crit Care Med. 2012 Nov 1;186(9):838-45. doi: 10.1164/rccm.201204-0645OC. Epub 2012 Jul 19.


Rationale: Reversal of sepsis-induced immunoparalysis may reduce the incidence of secondary infections and improve outcome. Although IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) restore immune competence of ex vivo stimulated leukocytes of patients with sepsis, effects on immunoparalysis in vivo are not known.

Objectives: To investigate the effects of IFN-γ and GM-CSF on immunoparalysis in vivo in humans.

Methods: We performed a double-blind, placebo-controlled, randomized study in 18 healthy male volunteers that received Escherichia coli endotoxin (LPS; 2 ng/kg, intravenously) on days 1 and 7 (visits 1 and 2). On days 2, 4, and 6, subjects received subcutaneous injections of IFN-γ (100 μg/day; n = 6), GM-CSF (4 μg/kg/day; n = 6), or placebo (NaCl 0.9%; n = 6).

Measurements and main results: In the placebo group, immunoparalysis was illustrated by a 60% (48-71%) reduction of LPS-induced tumor necrosis factor (TNF)-α plasma concentrations during visit 2 (P = 0.03), whereas the antiinflammatory IL-10 response was not significantly attenuated (39% [2-65%]; P = 0.15). In contrast, in the IFN-γ group, TNF-α concentrations during visit 2 were not significantly attenuated (28% [1-47%]; P = 0.09), whereas the IL-10 response was significantly lower (reduction of 54% [47-66%]; P = 0.03). Compared with the placebo group, the reduction in the LPS-induced TNF-α response during visit 2 was significantly less pronounced in the IFN-γ group (P = 0.01). Moreover, compared with placebo, treatment with IFN-γ increased monocyte HLA-DR expression (P = 0.02). The effects of GM-CSF tended in the same direction as IFN-γ, but were not statistically significant compared with placebo.

Conclusions: IFN-γ partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-γ is a promising treatment option to reverse sepsis-induced immunoparalysis.

Trial registration: NCT01374711.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Intravenous
  • Double-Blind Method
  • Endotoxins / administration & dosage
  • Endotoxins / immunology*
  • Granulocyte Colony-Stimulating Factor / immunology
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Humans
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology*
  • Immunocompromised Host*
  • Interleukin-18 / immunology
  • Interleukin-18 / therapeutic use
  • Male
  • Netherlands
  • Pilot Projects
  • Sepsis / complications
  • Sepsis / drug therapy
  • Sepsis / immunology*
  • Young Adult


  • Endotoxins
  • Interleukin-18
  • Granulocyte Colony-Stimulating Factor
  • endotoxin, Escherichia coli

Associated data